Journal Article

Whi2 is a conserved negative regulator of TORC1 in response to low amino acids

Hardwick, J. Marie, Metz, Kyle A., Diny, Nicola L., Stolp, Zachary D., Zhang, Yu, Sing, Cierra N., Dayhoff-Brannigan, Margaret, He, Ge, Wang, Guiqin, Zhao, Mingjun, Teng, Xinchen, Cheng, Wen-Chih, Aouacheria, Abdel, Chen, Xianghui

2018

Overview

Yeast WHI2 was originally identified in a genetic screen for regulators of cell cycle arrest and later suggested to function in general stress responses. However, the function of Whi2 is unknown. Whi2 has predicted structure and sequence similarity to human KCTD family proteins, which have been implicated in several cancers and are causally associated with neurological disorders but are largely uncharacterized. The identification of conserved functions between these yeast and human proteins may provide insight into disease mechanisms. We report that yeast WHI2 is a new negative regulator of TORC1 required to suppress TORC1 activity and cell growth specifically in response to low amino acids. In contrast to current opinion, WHI2 is dispensable for TORC1 inhibition in low glucose. The only widely conserved mechanism that actively suppresses both yeast and mammalian TORC1 specifically in response to low amino acids is the conserved SEACIT/GATOR1 complex that inactivates the TORC1-activating RAG-like GTPases. Unexpectedly, Whi2 acts independently and simultaneously with these established GATOR1-like Npr2-Npr3-Iml1 and RAG-like Gtr1-Gtr2 complexes, and also acts independently of the PKA pathway. Instead, Whi2 inhibits TORC1 activity through its binding partners, protein phosphatases Psr1 and Psr2, which were previously thought to only regulate amino acid levels downstream of TORC1. Furthermore, the ability to suppress TORC1 is conserved in the SKP1/BTB/POZ domain-containing, Whi2-like human protein KCTD11 but not other KCTD family members tested.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Amino acids / Amino Acids - metabolism / Animals / Biochemistry / Biochemistry, Molecular Biology / Biodiversity / Bioinformatics / Biology and Life Sciences / Biotechnology / Cancer / Cell cycle / Cell growth / Cellular Biology / Cercopithecus aethiops / Chlorocebus aethiops / Computer Science / COS Cells / Down-regulation / Funding / Gene Expression Regulation / Genes / Genetic screening / Genetic testing / Genetics / Genomics / Humans / Immunology / Intracellular Signaling Peptides and Proteins - genetics / Intracellular Signaling Peptides and Proteins - metabolism / Kinases / Laboratories / Life Sciences / Membrane Proteins - genetics / Membrane Proteins - metabolism / Molecular biology / Monomeric GTP-Binding Proteins - genetics / Monomeric GTP-Binding Proteins - metabolism / Mutation / Neurological diseases / Pharmaceutical sciences / Phosphoprotein Phosphatases - genetics / Phosphoprotein Phosphatases - metabolism / Physical Sciences / Populations and Evolution / Proteins / Public health / Research and Analysis Methods / Saccharomyces cerevisiae - genetics / Saccharomyces cerevisiae - metabolism / Saccharomyces cerevisiae Proteins - genetics / Saccharomyces cerevisiae Proteins - metabolism / Subcellular Processes / Transcription Factors - genetics / Transcription Factors - metabolism / Yeast